Immunomodulatory and toxic effects of free and liposome-encapsulated tumor necrosis factor alpha in rats.
Tumor necrosis factor alpha has potent immunomodulatory and antitumor activity, but its therapeutic applications may be limited by its significant host toxicity. We showed that liposome-encapsulated recombinant human tumor necrosis factor alpha (rHuTNF-alpha) retained full anticellular activity in vitro. We then assessed the immunomodulatory and toxic effects of two different doses of i.v. free or liposome-encapsulated rHuTNF-alpha in normal rats. Both free and liposome-encapsulated rHuTNF-alpha significantly enhanced alveolar macrophage- and blood monocyte-mediated interleukin 1 release and tumor cell lysis, as well as natural killer cell cytotoxicity, when compared to buffer-treated controls. However, administration of rHuTNF-alpha in liposomes substantially reduced tumor necrosis factor alpha-mediated toxicity. Animals receiving liposome-encapsulated rHuTNF-alpha showed significantly less tissue injury, gastric retention, and circulating leukocyte shifts than animals receiving free rHuTNF-alpha. In addition, liposome-based delivery significantly increased lung and liver uptake of rHuTNF-alpha. Therefore, liposome-encapsulated rHuTNF-alpha retains immunomodulatory activity, significantly reduces toxic inflammatory effects, and may allow targeting of tumor necrosis factor alpha to selected organs after i.v. administration.
Debs
R J
RJ
Cancer Research Institute, University of California, San Francisco 94143.
Fuchs
H J
HJ
Philip
R
R
Brunette
E N
EN
Düzgüneş
N
N
Shellito
J E
JE
Liggitt
D
D
Patton
J R
JR
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D004337:Drug Carriers; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008081:Liposomes; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D008081:Liposomes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha